J. Phys. Chem. 1985,89, 361-363
361
Thermodynamics of Molecular Association of Phenothiazines and Iodine. 2 A. R. Saksena* and Aradhanat Department of Chemistry, C.M.P.Degree College, Allahabad-211002. India (Received: February 2, 1984; I n Final Form: September 24, 1984)
Dielectric constant measurements have been made for various compositions of phenothiazines-iodine systems in benzene at a radio frequency of 1 MHz at 30 and 40 "C. A precise density determination of donoracceptor solutions has been made by a calibrated double-stem pycnometer. Kinetic and thermodynamic parameters have been evaluated to interpret 1:l molecular association. UV spectra have been used to support the mechanism. A correlation has been proposed to interpret the drug response in the receptor phase.
Introduction The neuroleptic drugs probably act in the brain neurons without any degradation during their progress in the human body.' Therefore, physical interactions, e.g., molecular complexes or collisional complexes, charge transfer complexes, or H bonding with biological receptors, is possible. Charge transfer complex formation which plays a major role especially in the pharmacological action of drugs2p3has been worked out by several workers. Saucin and Van De Vorst4 have investigated spectrophotometrically the interaction of neuroleptic drugs with chloranil in a 50% acetone-ethanol mixture and have compared the drug response with the electron-donating strength of each drug in the formation of the chloranil ion in solution. The results show a total absence of charge transfer interaction at the activity site and have suggested a reinvestigation of the drug's activity with some other electron acceptors. Iodine, a u acceptor, has been selected for this study. It is present in the biophase and can interact with phenothiazines during their passage through the human body. Generally, these drugs are insoluble in water and hence benzene has been selected as a solvent for the study of the donor-acceptor systems. The dipolemeter cell has a 2-3-pF capacity and, therefore, studies in acetone-ethanol solutions are not possible. 13-, I-, and Bz-12 and ion pair formation have been excluded due to the fairly low concentration of iodine and the higher concentration of drug in the system. The action of iodine is very different in a nonpolar solvent than in a polar solvent. The scope of this paper has been limited only to kinetic and thermodynamic data. UV studies at room temperature support the action of iodine during the molecular association with the drugs. Chemicals Used Benzene (AR, B.D.H.) was distilled in a quick-fit vertical column. The fraction distilling between 79 and 80 OC was collected and kept overnight in a desiccator. M I S . May & Baker Ltd., London has supplied free samples of the drugs chloropromazine hydrochloride, prochloroperazine mesylate, promazine hydrochloride, thioproperazine mesylate, and pericyazine. The first four drugs were treated with dilute NaOH, filtered through a sintered glass crucible, and dried in an oven at low temperatures. The purity of the drug was improved by recrystallization from their saturated alcohol and acetone solutions (50%). Pericyazine was recrystallized from its saturated solution in cyclohexane. All drugs were kept in a vacuum desiccator for 48 h before use. Iodine (GR, Merck) was used without further purification. Experimental Section A Toshniwal RL09 dipolemeter operating at a frequency 1 M H z has been used to determine the dielectric constant of the solvent and solutions. It operates on heterodyne beat principle.5 The temperature of the cell is controlled by circulating water from 'Presently Research Scholar at Allahabad University, Allahabad-211002, India.
a NBE type ultrathermostat which is properly insulated and has a precision of *0.1 O C . The calibration procedure for the dipolemeter and pycnometer has been described in our earlier paper in detail6 The thermostat was properly insulated by an external Jacket and the rubber tubings from the outlet of thermostat to the inlet of dipolemeter were covered with cotton to reduce the possibility of any thermal loss. The standard error has been determined by checking the density and dielectric constant evaluated from the regression coefficients of pycnometer and dipolemeter for a known nonpolar solvent of high purity. The uncertainty found is of the order of 0.01% in d and e values. Donor (lW3 to 10-4 M) and acceptor M) have been mixed in a 25-mL volumetric flask, keeping the concentration of donor constant while that of the acceptor is varied (at least seven compositions have been made). Measurements of the dielectric constant and density have been made at 30 and 40 OC. UV spectra have been recorded at room temperature on Beckmann-DU spectrophotometer between 200 and 700 nm. Donor-acceptor solutions of a system have been recorded on different scales in order to obtain better spectra. Benzene as a reference and a 1-cm cell have been used throughout thii work. Since spectra have been recorded on separate plots, various peaks and bands were analyzed qualitatively. It is difficult to reproduce all spectra for all systems on a single chart. The analysis has been done keeping in mind the other spectral data available to the authors.
Calculations The polarization, P, of a donoracceptor solution can be related to the dielectric constant c by the Clausius-Mosotti equation
-M- E-- 1
d e+2
- p = P x ( W x - A W ) + Py(Wy-AW)
+ P2W2+ PIW,
(1)
where WiMl
M=
+ WxMx+ WyMy 1-AW
l-AW=Wx+Wy+Wl
(2) (3)
Subscripts 1,2, x, and y refer to the solvent, complex, donor, and acceptor, respectively. The terms M , d, P, W, and AWrefer to the molecular weight, density, polarization, weight fraction, and (1) Dresse, A. Thesis, Liege, Belgium, 1967. (2) Szent-Gyorgi, A. "Introduction to a Sub-Molecular Biology"; Academic Press: New York, 1960. (3) Cier, A.; Cuisinaud, G. Ann. Pharm. Fr. 1968, 26, 615. (4) Saucin, M.; Van De Vorst, A. Biochem. Pharmacol. 1972, 21, 2673-80. ( 5 ) Smith, J. W. "Electric Dipole Moments"; Butterworths: London, 1955 p 34. (6) Aradhana; Saksena, A. R.J . Mol. Liq. 1983,26,197-209; Ind. J. Pure Appl. P h p . 1984, 22, 342-45.
0022-3654/85/2089-0361$01 .SO10 0 1985 American Chemical Society
362 The Journal of Physical Chemistry, Vol. 89, No. 2, 1985
Saksena and Aradhana
TABLE I: Kinetic and Thermodynamic Parameters for the 1:l Molecular Association of Phenothiazines with Iodine and Drug Response Ap303, AF03,3, a0303? a0313, AHo, K:Y( TI), K,”Y(T2), dose,” drug kcal mol-’ kcal mol-’ eu eu kcal mol-’ mol-’ mol-’ mg/kg -3.75 -3.80 -3.90 -3.88 -4.05
pericyazine thioproperazine chloropromazine prochloroperazine promazine
-3.88 -3.90 -4.04 -4.03 -4.19
-49.68 -49.40 -48.80 -48.93 -48.64
-47.68 -47.40 -46.80 -48.42 -46.62
-18.8 -18.7 -18.6 -18.7 -18.8
508.00 542.61 635.00 635.00 833.65
512.78 555.60 666.00 661.45 846.66
0.25 2.00 0.73
“Dose of each drug required to reduce the self-stimulation behavior of the rates by 50% (ref 4). Uncertainty in K:Y is approximately 1%. Note: Detailed tables containing d , e, and P data for all systems are available from the authors.
weight fraction of complex, respectively. Foster’ has pointed out that the association constant K$Y can be evaluated from the following equation:
P (P,* - P A
=1+-
MY K$Y Wyd
(4)
where
AP = P2 - P, - Py
(5)
P - P,WY - PlW, P,* =
wx
(6)
Here, P,* is the apparent polarization constant when no complex formation is assumed. Also P,* and P, are the values extrapolated to infinite dilution. A P is for 1 mol of complex formed. A plot of (P,* - PJI vs. W f l &I is a straight line with an intercept of A P ’ and a gradient of MyIK$Y. AP gives the value of K$Y. In our calculations, points far away from the straight line have been rejected. The intercept C and slope m have been evaluated by a graphical method. Since most of the points fall on a straight line, the least-squares method has not been used. The uncertainty in the K$Y value is not appreciably affected by the graphical method. The linearity of the plot suggests (1:l) molecular association and that the Bensi-Hildebrand* equation is applicable to represent the molecular association. The association coefficient is actually a quotient because the activity coefficients have not been considered. The possibility for a 2: 1 complex has been excluded due to the fairly dilute solutions. The enthalpy of dissociation, AHo, is the most commonly used parameter and is obtained from the variation of K$Y with absolute temperature from the Van’t Hoff reaction isochore. Thus, heat absorbed by the system at constant volume but at two temperatures can be calculated from the following integrated form of Van’t Hoff isochore equation between definite limits: In KcxY(Tl) In KtY(Tz) =RZ ( + $ ) ( 7 ) where R is the gas constant, K$Y is in inverse concentration (M-l), and AHo is in kcal mol-I. T , and T2 are 303 and 313 K respectively. Other parameters which can be obtained are the standard free energy, A P (kcal mol-’) given by Van’t Hoff reaction isotherm: AFo = -RT In KcXY
(8)
and the standard entropy, ASo (eu), given by Gibbs-Helmholtz equation under standard conditions as follows: AFo = AHo - TASO (9) All the kinetic and thermodynamic parameters are shown in Table I. Since these data have been evaluated at two temperatures only, there are chances of greater uncertainty even when the estimate of AHo lies within the energy conditions for a charge transfer interaction between donor and acceptor molecules. (7) Foster, R. “Organic Charge-Transfer Complexes”; Academic Press: London, 1969. (8) Bensi, H. A.; Hildebrand, J. H . J . Am. Ckem. SOC.1969, 71,2703.
Discussion In the calculation of the association constant, it has been assumed that all iodine molecules in the solutions are complexed with the donor molecules and that the concentrations of free iodine, the iodide ion, I-, triiodide ion, 13-, the iodine complex with benzene, CTS, and ion pairs of the D+A- type are negligibly small. Solutions of amino acid with iodine in water exhibit spectral changes which proceed in two stage^.^ In the first stage, the iodine, Iz, band reduces in intensity with a gradual increase in the triiodide ion, I
